The dominant therapeutic approaches that are currently employed to treat cancer include surgical removal of primary tumors, tumor irradiation, and parenteral application of anti-mitotic cytotoxic agents. The continued dominance of these long established therapies is mirrored by the lack of improvement in survival rates for most cancers. In addition to limited clinical success, devastating side effects accompany classic therapies. Both radiation- and cytotoxic-based therapies result in the destruction of rapidly dividing hematopoietic and intestinal epithelial cells leading to compromised immune function, anemia, and impaired nutrient absorption. Surgical intervention often results in a release of tumor cells into the circulation or lymph systems from which metastatic tumors can subsequently be established.
Metastasis still remains the main cause of death for most cancer patients. Despite years of research, the genetic mechanisms involved in the process are ill defined. Such information is of special importance in cancer prognosis given the uncertain course of the disease. The mechanisms which regulate the growth of the cancer cell are of particular relevance to the development of strategies for the treatment of metastatic cancer. Individual patients exhibit extreme variation in cancer progression. In some patients the cancer remains localized, whereas in other the cancer metastasizes quickly. Stromal-epithelial interactions (mediated through cytokine and other growth factors) with the extracellular matrix play a role in development of metastatic cancer.
Macrophage migration inhibitory factor (MIF) is a major mediator of innate immunity and inflammation (Calandra, Nat Rev Immunol, 3:791-800 (2003)) and represents a potential therapeutic target for multiple inflammatory, infectious, and autoimmune diseases, including cancer (Leech et al., Arthritis Rheum, 42:1601-1608 (1999); Morand, Intern Med J, 35:419-426 (2005); Bucala et al., Immunity, 26:281-285 (2007)). MIF is a homotrimeric multifunctional protein that could function as a cytokine, hormone, and/or enzyme. Three non-physiological substrates are reported for MIF tautomerase activity: the D-dopachrome methyl ester, phenyl pyruvic acid, and hydroxyphenyl pyruvic acid (Rosengren et al., FEBS Lett, 417:85-88 (1997); Sugimoto et al., Biochemistry, 38:3268-3279 (1999)). Although the link between the enzymatic activity of MIF and its biological function remains controversial, there is sufficient evidence to suggest that MIF's tautomerase activity and/or catalytic site modulates some of its proinflammatory function(s) (Dios et al., J Med Chem, 45:2410-2416 (2002); Swope et al., EMBO J, 17:3534-3541 (1998)). Therefore, blocking the enzymatic activity of MIF as a means of attenuating and/or neutralizing its cellular function(s) has emerged as a promising strategy to treat MIF-related diseases, including septic shock, rheumatoid arthritis, atherosclerosis, and multiple sclerosis.
MIF's 3D structure was resolved in 1996. Subsequent biochemical and mutagenesis studies have allowed the identification of the key residues involved in forming the catalytic site and in regulating MIF's tautomerase activity (Johnson et al., Biochemistry, 38:16024-16033 (1999)). Since that time, significant efforts have attempted to identify small-molecule modulators of MIF by targeting its tautomerase activity (Orita et al., Curr Pharm Des, 8:1297-1317 (2002)). The availability of X-ray structures of the MIF trimer and the tautomerase catalytic site has facilitated these efforts and has stimulated great interest in rationally developing structure-based inhibitors. The first MIF inhibitors were identified by testing different D-dopachrome derivatives or phenyl pyruvic acid analogs (Zhang et al., Bioorg Med Chem Lett, 9:3193-3198 (1999)). In the past decade, several classes of MIF inhibitors have been developed by introducing modifications on substrate analogs and by screening focused libraries of natural products (Orita et al., Curr Pharm Des, 8:1297-1317 (2002); Orita et al., J Med Chem, 44:540-547 (2001)). Several of these inhibitors were later shown to modulate MIF's biological activities (e.g., IS01 and OXIME11) in cellular models and in vivo (Al-Abed et al., J Biol Chem, 280:36541-36544 (2005); Dabideen et al., J Med Chem, 50:1993-1997 (2007)).
Because of the shortcomings of classic treatment regimens, there is a need in the art for improved anticancer therapies. One potential and underdeveloped therapeutic area includes MIF inhibitors.